Milk thistle is a plant whose fruit and seeds have been used for more than 2,000 years as a treatment for liver and biliary disorders.

The active substance in milk thistle, silymarin, is a complex mixture of flavonolignans, primarily consisting of the following isomers: silybin (consisting of silybins A and B), isosilybin (consisting of isosilybins A and B), silychristin (also known as silichristin), and silydianin (also known as silidianin). In the literature, silybin is often referred to as silibinin.

Many of the medical and scientific terms used in the summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.

Reference citations in some PDQ CAM information summaries may include links to external Web sites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the Web sites, or of any treatment or product, by the PDQ Cancer CAM Editorial Board or the National Cancer Institute.

General Information

The botanical name for milk thistle is Silybum marianum (L.) Gaertn. Milk thistle is also referred to as holy thistle, Marian thistle, Mary thistle, Our Lady’s thistle, St. Mary thistle, wild artichoke, Mariendistel (German), and Chardon-Marie (French). The plant is indigenous to Europe but can also be found in the United States and South America. Traditionally, the leaves have been used in salads, and the fruit of the flower has been roasted as a coffee substitute. The seeds of milk thistle are the medicinal parts of the plant.[1] The primary active constituent of milk thistle is silymarin, which is composed of the following isomers: silybin (consisting of silybins A and B), isosilybin (consisting of isosilybins A and B), silychristin, and silydianin. Most supplements are standardized according to their silybin content. Silybin and isosilybin are both mixtures of two diastereomers, silybins A and B and isosilybins A and B, respectively.[2,3] Special formulations of silybin have been developed to enhance the bioavailability of the herbal product; these forms are sold under the names Legalon, silipide, and Siliphos. Because of milk thistle’s lipophilic nature, it is usually administered in capsule or tablet form rather than as an herbal tea. In Europe, silybin is administered intravenously as the only effective antidote for Amanita phalloides (Fr.).[4] Humans exposed to this mushroom toxin develop serious liver failure that ultimately progresses to death.

Several companies distribute milk thistle as a dietary supplement. In the United States, dietary supplements are regulated as foods, not drugs. Therefore, premarket evaluation and approval by the Food and Drug Administration (FDA) are not required unless specific disease prevention or treatment claims are made. Because dietary supplements are not formally reviewed for manufacturing consistency, ingredients may vary considerably from lot to lot; in addition, there is no guarantee that ingredients identified on product labels are present at all or are present in the specified amounts. It is important to note that the FDA has not approved the use of milk thistle as a treatment for cancer patients or patients with any other medical condition.

To conduct clinical drug research in the United States, researchers must file an Investigational New Drug (IND) application with the FDA. The IND application process is confidential, and IND information can be disclosed only by the applicants. To date, only one investigator has announced holding an IND to study milk thistle as an adjunct cancer treatment.

Despite milk thistle’s long history of being used to treat liver and biliary complaints, it was not until 1968 that silymarin was isolated from the seeds of the plant, and it was proposed that silymarin might be the active ingredient.[5] Silymarin was later determined to be a flavonolignan that is composed of four structurally similar compounds: silybin, isosilybin, silydianin, and silychristin.[2] Researchers have investigated the role that silibinin may play in the treatment of hepatitis and cirrhosis. Most studies have investigated the isolated compound silymarin or its most active isomer silybin, rather than the herbal plant in its whole form.

Silymarin is most well known for its purported effects on the liver. In laboratory studies, silymarin has been found to stabilize cellmembranes, thus preventing toxic chemicals from entering the cell.[4,6-8] Laboratory studies have also demonstrated that silymarin stimulates synthesis and activity of enzymes responsible for detoxification pathways and exhibits antioxidant properties.[7-18] Specifically, silymarin has been shown to stimulate the glutathione S-transferase pathway and alter the intracellular concentration of glutathione (a potent antioxidant). Silymarin has also been shown to neutralize a wide range of free radicals.

Laboratory experiments conducted using cancer cell lines have suggested that silibinin enhances the efficacy of cisplatin and doxorubicin against ovarian and breast cancer cells.[19] Silybin appears to have direct anticancer effects against prostate, breast, and ectocervical tumor cells.[20] Silybin may also affect the cell cycle in cancer cells by slowing down cell growth, as demonstrated with prostate cancer cell lines.[21] Laboratory studies using leukemia cell lines found that silybin did not stimulate growth of leukemia cells.[22]

No human clinical trials on milk thistle or silymarin as a cancer treatment or as an adjunctive therapy in individuals with cancer have been published. Most clinical trials have investigated silymarin’s effectiveness in the treatment of patients with hepatitis, cirrhosis, or biliary disorders.[23-32] These studies have employed a wide range of doses (120–560 mg /day) and have yielded conflicting results.Many of the well-designed, large-scale trials have reported a beneficial effect rather than no effect. The most commonly reported adverse effects are a mild laxative effect and gastrointestinal upset.

Marcelli R, Bizzoni P, Conte D, et al.: Randomized controlled study of the efficacy and tolerability of a short course of IdB 1016 in the treatment of chronic persistent hepatitis. European Bulletin of Drug Research 1 (3): 131-5, 1992.

History

Milk thistle has been used for more than 2,000 years, primarily as a treatment for liver dysfunction. The oldest reported use of milk thistle was by Dioscorides, who recommended the herb as a treatment for serpent bites.[1] Pliny the Elder (A.D. 23–79) reported that the juice of the plant mixed with honey is indicated for “carrying off bile.”[1,2] In the Middle Ages, milk thistle was revered as an antidote for liver toxins.[1,2] The British herbalist Culpepper reported it to be effective for relieving obstructions of the liver.[1,2] In 1898, eclectic physicians Felter and Lloyd stated the herb was good for congestion of the liver, spleen, and kidney.[1,2] Native Americans use milk thistle to treat boils and other skin diseases. Homeopathic practitioners used preparations from the seeds to treat jaundice, gallstones, peritonitis, hemorrhage, bronchitis, and varicose veins.[2] The German Commission E recommends milk thistle use for dyspeptic complaints, toxin-induced liver damage, hepaticcirrhosis, and as a supportive therapy for chronicinflammatory liver conditions.[3]

Although many of these studies have produced encouraging results, none of the findings have been replicated in human clinical trials.

Laboratory data suggest that silymarin and silybin protect the liver from damage induced by toxic chemicals. Animal studies have found that liver cells treated with silybin and then exposed to toxins do not incur cell damage or death at the same rate as liver cells that are not treated with silybin. This finding suggests that silybin can prevent toxins from entering the cell or effectively exports toxins out of the cell before damage ensues.[11,27-31] Alternatively, this may be related to the effect of silymarin on detoxification systems. In vitro data have shown silybin to stimulate and/or inhibit phase I detoxification pathways in silybin-treated human liver cells.
However, this effect was found to be dose-dependent, and these levels are not physiologically attainable with the current manufacturer dose recommendations.[32,33]

Silymarin has been shown to stimulate phase II detoxification pathways in mice. Administration of silymarin (100 or 200 mg /kg body weight/day) to SENCAR mice for 3 days significantly increased glutathione S-transferase activity in the liver (P < .01–.001), lung (P < .05–.01), stomach (P < .05), small bowel
(P < .01), and skin (P < .01). This effect appeared to be dose-dependent.[34] Administration of silymarin to rats challenged with a toxin (50 mg/kg body weight) resulted in higher levels
of glutathione in liver cells, decreased levels of oxidative stress (measured by malondialdehyde concentrations), and less elevated liver function tests (measured by levels of aspartate aminotransferase [AST] and alanine aminotransferase [ALT]).[31] Silymarin and silybin have also been found to accelerate cell regeneration in the liver through stimulation of precursors to DNA synthesis and enhancement of production of the cellular enzymes required for synthesis of DNA.[35-40] Laboratory studies have also shown silymarin and silybin to be potent antioxidants.[28,29,41-48] Silymarin has been shown to mitigate oxidative stress in cells treated with pro-oxidant compounds.

A number of laboratory studies have investigated the effect of silymarin or silybin on the efficacy and toxicity of chemotherapy agents or have measured their direct cytotoxic activity. In an investigation of the effect of a variety of flavonoids on the formation of DNA damage, silymarin did not induce DNA damage in colon (Caco-2) cells, hepatoma (HepG2) cells, and human lymphocytes.[12] At higher concentrations of silymarin (400–1,000 μmol/L) DNA damage was induced in an epithelial cell line (HeLa cells). At higher concentrations (1,000 μmol/L) DNA damage was observed in human lymphocytes. Cell growth was inhibited as the flavonoid concentration was increased in human lymphocytes and HeLa cells. Only at very high concentrations was cell viability affected by silymarin in HepG2 cells. Although this study demonstrated that the flavonolignans of Silybum marianum (L.) are capable of inhibiting cellular proliferation and inducing DNA strand breaks, the results were obtained at very high concentrations that may be difficult to achieve in humans. This study also showed that silymarin does not stimulate cell growth in the HeLa, Burkitt lymphoma, and human hepatoma cell lines.

Silymarin has also been investigated as a possible adjunctive agent in mitigating some of the toxicity associated with chemotherapy agents. Silybin and silychristin exerted a protective effect on monkey kidney cells exposed to vincristine and especially cisplatin chemotherapy.[49] Silybin (200 mg/kg body weight) administration with cisplatin in rats resulted in statistically significant reductions in measures of kidney toxicity.[50] Significant decreases in weight loss, faster recovery of urinaryosmolality measures, and depressions in the increase in activity of urinary alanine aminopeptidase ([AAP], a marker of kidney toxicity) were observed. Silybin had no effect on magnesium excretion or glomerular function. Silybin (2 g /kg body weight) administration in rats receiving cisplatin prevented reductions in creatinine clearance, increases in ureaplasma levels, and large increases in urinary AAP.[51] No effect on magnesium excretion was observed. Silybin did not interfere with the antineoplastic effects of cisplatin or ifosfamide in germ cell tumors. In experiments with ovarian and breast cancer cell lines, silybin potentiated the effect of cisplatin and doxorubicin.[13] IdB 1,016, a form of silybin bound to a phospholipid complex, was found to enhance the activity of cisplatin against A2780 ovarian cancer cells but had no effect on its own.[52] Silybin increased the chemosensitivity of DU 145 prostate cancer cells resistant to chemotherapy.[53]

Studies have also investigated the effect of silymarin on tumor initiation and promotion. Silymarin appears to have a chemopreventive effect through perturbations in the cell cycle, altering cell signaling that induces cellular proliferation, affecting angiogenesis, or through its anti-inflammatory properties.[1,7,13,19,54] These findings have been supported in human prostate, breast, ectocervical, ovarian, hepatic, leukemia, and epidermoid cell lines.[4,7,9,10,15,55] An investigation of the effect of silymarin on ultraviolet B radiation-induced nonmelanoma skin cancer in mice found that silymarin treatment significantly reduced tumor incidence (P < .003), tumor multiplicity (P < .0001), and tumor volume (P < .0001).[19] These findings suggest that silymarin plays a prominent role in the reduction of cancer cells and in preventing the formation of cancer cells. A number of studies have investigated the mechanism through, which silymarin may affect tumor promotion in mouse skin tumor models. Studies have found that silymarin reduces transcription of markers of tumor promotion and activity,[19] inhibits transcription of tumor promoters,[56] stimulates antioxidant activities,[19,23] interferes with cell signaling,[55] inhibits inflammatory actions,[19,22] and modulates cell-cycle regulation.[57]

In prostate cancer cell lines, silybin has been shown to inhibit growth factors and stimulate cell growth,[1-3,5] promote cell cycle arrest,[1,4] and inhibit antiapoptotic activity.[53] In rats with azoxymethane -induced colon cancer, dietary silymarin resulted in a reduction in the incidence and multiplicity of adenocarcinoma of the colon in a dose-dependent manner.[25,26] Dietary silymarin had no effect on small intestinal adenocarcinoma,[26] but exerted a preventive effect in mice with N-butyl-N-(4-hydroxybutyl) nitrosamine –induced bladder cancer [24] and in F344 rats with 4-nitroquinoline 1-oxide –induced cancer of the tongue.[17] Dietary silybin administered to nude mice with prostate carcinoma increased production of insulin-like growth factor-binding protein-3 in the plasma of mice and significantly inhibited tumor volume (P < .05).[2] Silibinin administered twice daily reduced the growth of colorectal tumor xenografts in mice for a period of 6 weeks.[58,59]

In a double-blind, placebo-controlled trial, 50 children who were undergoing treatment for acute lymphoblastic leukemia and who had chemotherapy -related hepatotoxicity were randomly assigned to receive silymarin or placebo for a 4-week period.[3] Four weeks following completion of the intervention, the silymarin group had a significantly lower aspartate aminotransferase (AST) (P = .05) and a trend towards a significantly lower alanine aminotransferase (ALT) (P = .07). Fewer chemotherapy dose reductions were observed in the silymarin group compared to the placebo group; however, the difference was not significant. No adverse events were reported.

Most clinical trials of milk thistle have been conducted in patients with either hepatitis or cirrhosis. Other studies have investigated milk thistle in patients with hyperlipidemia, diabetes, and Amanita phalloides mushroom poisoning. Ten randomized trials [3-12] have been reported in patients with hepatitis or cirrhosis, and one randomized trial has reported the use of silymarin as a prophylaxis to iatrogenic hepatictoxicity.[13] Endpoints for these trials have included serum levels of bilirubin and/or the liver enzymes AST and ALT, as higher levels are an indicator of liver inflammation, damage, or disease. The lowering of these serum levels is a sign of an improving condition. In patients with hepatitis A and B, one clinical trial found silymarin (140 mg daily for 3–4 weeks) resulting in lower levels of AST, ALT, and bilirubin by day 5, compared with a placebo group.[14] In another randomized, placebo-controlled study of patients with viral hepatitis B, silymarin (210 mg daily) had no effect on course of disease or enzyme levels.[7]

A randomized, controlled trial supported by the National Institute of Diabetes and Digestive and Kidney Diseases examined patients with chronic hepatitis C who had failed prior antiviral therapy. All patients had advanced chronic liver disease consisting of histologic evidence of either marked fibrosis or cirrhosis. The Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis trial used a half dose of pegylated interferon versus no treatment; the treatment was to be administered for 3.5 years.[12] The aim was to reduce progression of chronic hepatitis C, particularly in the development of hepatocellular carcinoma. Among 1,145 study participants, 56% had never taken herbals, 21% admitted past use, and 23% were using herbals at enrollment. Silymarin constituted 72% of the 60 herbals used at enrollment. Users had significantly fewer symptoms and a better quality of life than nonusers. In follow-up, silymarin use was associated with reduced progression of fibrosis to cirrhosis but without an impact on clinical outcome.[15]

Although there are many reports of the use of herbals for the treatment of chronic liver diseases, most treatment trials have suffered from poor scientific design, uncertainty of the required dosage of herbals, and an insufficient number of study participants. A recent review of complementary and alternative medications (CAM) to treat liver diseases focused on the classification, epidemiology, and the philosophy of CAM and reviewed the criteria needed to conduct a scientifically valid research study focusing on herbal products.[16]

There has been skepticism regarding the evidence that silymarin has a direct impact on the hepatitis C virus (HCV)—some studies suggest that it does, but most studies are unable to confirm these reports. However, at least two articles in major journals have suggested that silymarin or its congeners may inhibit HCV. In one report, investigators found that a standardized silymarin extract inhibited tumor necrosis factor -alpha in anti-CD3–stimulated human peripheral blood mononuclear cells and nuclear factor-kappa B-dependent transcription in human hepatoma Huh-7 cells.[17] Silymarin also displayed prophylactic and therapeutic effects against HCV infection and when combined with interferon-alpha, was more inhibitory of HCV replication than was interferon alone. This indicates that silymarin has anti-inflammatory and antiviral effects in patients with chronic hepatitis C.

In a case series /phase I study, patients with HCV were treated with intravenous silibinin with and without PEG-interferon and ribavirin.[18] In the case series, 16 HCV nonresponder patients were administered intravenous silibinin in a dose of 10 mg/kg/day for 7 days. Subjects then began treatment with oral silibinin in combination with PEG-interferon and
ribavirin for 12 weeks. At the end of the study period, all patients were positive for HCV RNA, but 5 of 13 completed patients had reductions in HCV RNA. Significance was not reported. In the same study, the authors presented results of a phase I study in which 20 patients were administered 5 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg of silibinin for 14 days in combination with PEG-interferon and ribavirin (initiated on day 8). A significant drop in HCV RNA was observed on day 7 in patients administered the 10 mg/kg, 15 mg/kg, and 20 mg/kg doses of silybinin. Further declines were observed in HCV RNA with administration of PEG-interferon and ribavirin. Except for mild gastroenteritis, intravenous silibinin monotherapy was well tolerated.

Patients in a phase I pharmacokinetics study for the evaluation of absorption characteristics and determination of effective doses received increasing oral doses of silymarin.[19] A subsequent multicenter, double-blind, placebo-controlled trial, involving 154 patients with chronic HCV infection who had previously failed interferon-based treatment and had raised ALT levels, was performed.[20] Patients were randomly assigned to receive 420 mg of silymarin, 700 mg of silymarin, or a matching placebo orally 3 times per day for 24 weeks, with the aim of reducing ALT levels to less than 40 U/L or less than 65 U/L if this was at least a 50% decline from the baseline level. In this study, silymarin given orally in higher-than-usual doses failed to significantly reduce serum ALT levels. No significant adverse effects were associated with silymarin. In one of the largest observational studies involving 2,637 patients with chronic liver disease, 8-week treatment with 560 mg/day of silymarin resulted in reductions of serum AST, ALT, and gamma-glutamyltranspeptidase ([GGT], a marker of bile duct disease) and a decrease in the frequency of palpablehepatomegaly.[21]

Another published report describes the use of silybinin as the only effective antidote in patients with liver damage from Amanita phalloides (Fr.) Link poisoning.[22] Patients were administered doses of 35 to 55 mg/kg body weight, with no reports of adverse events. A recent retrospective review of the treatment for Amanita phalloides poisoning suggests that silymarin continues to be a promising drug in the treatment of this mushroom poisoning.[23] The beneficial effect of silymarin on liver histology suggests it has a role in the prevention of hepatitis and/or hepatocellular carcinoma; however, no clinical trials in humans have investigated these uses of silymarin.

Clinical Studies Investigating Silymarin in the Treatment or Prevention of Liver Disease

aNumber of patients treated plus number of patients controlled may not equal number of patients enrolled; number of patients enrolled = number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated = number of enrolled patients who were administered the treatment being studied AND for whom results were reported; historical control subjects are not included in number of patients enrolled.

bNine patients were excluded from the final analysis (seven patients missed appointments, and two patients were missing data requirements).

cStudy investigated dose-response relationships. Patients were randomly assigned to receive 80 mg 2 times a day (n = 20), 120 mg 2 times a day (n = 20), or 120 mg 3 times a day (n = 20). The effective dose was 120 mg 2 times a day and 120 mg 3 times a day.

dPatients were randomly assigned to the misoprostol and silymarin groups. Twelve nonrandomized patients served as controls.

eFifteen patients were lost to follow-up, 18 patients were deceased, and 42 patients withdrew from the study (adverse events, noncompliance, and voluntary withdrawal).

fEleven patients did not complete the trial (voluntary withdrawal, disease progression, and one adverse event).

Adverse Effects

Human studies of silymarin have shown minimal adverse effects in multiple large, blinded, placebo-controlled, randomized studies. Silymarin is well tolerated, with only rare reports of a mild laxative effect. Mild allergic reactions have been seen at high doses (>1,500 mg /day), although the details of these allergic reactions were not reported.[1] A recent case report from Australia described a reaction to a milk thistle extract that included intermittent episodes of sweating, abdominal cramping, nausea, vomiting, diarrhea, and weakness.[2] All symptoms resolved when the silymarin was discontinued. The authors suggested that the capsules were contaminated; the type of contamination was unknown.

According to the German Commission E, there are no reported side effects with milk thistle within the recommended doses. Rare cases of milk thistle having a laxative effect have been reported. Human studies have reported stomach upset, heartburn, and transient headaches; however, none of these symptoms were attributed to supplementation with milk thistle, and supplementation was not discontinued.[3] One human dosing study reported nausea, heartburn, and dyspepsia in patients treated with 160 mg/day, dyspepsia in patients treated with 240 mg/day, and postprandial nausea and meteorism in patients treated with 360 mg/day. None of these side effects were dose related.

Silymarin has been well tolerated in high doses. Silymarin has been used in pregnant women with intrahepaticcholestasis at doses of 560 mg/day for 16 days, with no toxicity to the patient or the fetus.[4] The published data on silymarin use in children focuses on intravenous doses of 20 to 50 mg/kg body weight for mushroom poisoning.[5] Silymarin has also proved nontoxic in rats and mice when administered in doses as high as 5,000 mg/kg body weight. Rats and dogs have received silymarin at doses of 50 to 2,500 mg/kg body weight for a 12-month period. Investigations, including postmortem analyses, showed no evidence of toxicity.

It is not known whether milk thistle may reduce, enhance, or have no effect on the effectiveness of chemotherapy. Silymarin decreases the activity of the cytochrome P450 enzyme system, which is involved in the clearance of certain chemotherapy drugs.[6] However, the dose at which inhibition is observed is high and not achieved with oral intake of silymarin.[7] One study investigated the effects of silymarin on the pharmacokinetics of irinotecan. Oral administration of milk thistle (200 mg, a clinically relevant dose, 3 times per day) had no significant effects on the pharmacokinetics of irinotecan. The authors concluded that the recommended doses of milk thistle are too low to affect activity of CYP3A4 or UGT1A1 enzyme pathways.[8]

Theoretically, milk thistle may also interact adversely with chemotherapy drugs that exert their cytotoxic effects through the generation of free radicals. Silymarin and its metabolite inhibit P-glycoprotein–mediated cellular efflux, leading to the potentiation of doxorubicin cytotoxicity.[9] No trials have been performed to support or negate these theoretical considerations. No effects on indinavir and alcohol pharmacokinetics have been observed. Enhancement of antiarrhythmic effects of amiodarone in rats has been observed.[9]

Describe clinical findings in sufficient detail for a meaningful evaluation to be made.

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. A level of evidence score cannot be assigned to milk thistle because there has been insufficient clinical research to date. For an explanation of the scores and additional information about levels of evidence analysis of CAM treatments for cancer, refer to Levels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine.

Given the limited amount of human data, the use of milk thistle/silymarin as a treatment for cancer patients cannot be recommended outside the context of well-designed clinical trials.

Changes to This Summary (03/26/2015)

The PDQcancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of milk thistle in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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This summary is reviewed regularly and updated as necessary by the PDQ Cancer Complementary and Alternative Medicine Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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The lead reviewers for Milk Thistle are:

John A. Beutler, PhD (National Cancer Institute)

Kara Kelly, MD (Columbia University)

Elena J. Ladas, PhD, RD (Columbia University)

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